Introduction:
A tumor microenvironment (TME) is an environment present around a tumor. The cells of tumors bring about molecular, cellular, and physical changes in the tissues of an affected individual. The emerging TME is a complex and continuously present entity. This environment includes surrounding blood vessels, immune cells, fibroblasts, signaling molecules, and extracellular matrix.
What Is a Tumor Microenvironment?
The tumor is a mass formed by a group of abnormal cells. Tumors may be formed in bones, skin, tissues, organs, and glands. It may be benign or malignant. These tumors may be life-threatening and require treatment.
TME is a surrounding entity of a tumor. It is formed by the tumor and dominated by tumor-induced interactions. Tumors in humans are infiltrated by inflammatory cells. The size and composition of inflammatory cells vary from one tumor to another. Its presence shows that the body of an affected individual is not ignorant of the developing tumor. These try to interfere with the growth of a tumor. This process is called immune surveillance. This shows that inflammatory cells in tumors try to identify the tumor cells and try to remove them from the body.
Many studies have shown that inflammatory cells in tumors indicate better prognosis and improved survival of an affected individual. Some studies have shown that there is no correlation between lymphocytic infiltration and the prognosis of the tumors of immune cell infiltration. Hence, it has remained unexplained for many years.
The functional properties of tumor-infiltrating lymphocytes (TIL) represented the major component of immune infiltrates in tumors. Hence, TIL obtained from tumor tissues represents an inhibited proliferation in response to mitogens or antigens, decreased signaling through T cell receptors, decreased ability to mediate cytotoxicity of tumor targets, and reduced ability to produce Th1-type cytokines on stimulation with tumor antigens. The functional status of TIL is independent and gives the prognosis and survival of individuals affected with malignancy (cancer).
Methods used to study functions, attributes of immune cells, and understanding of their interactions with other cells enlarged, the role of microenvironment in health and disease was appreciated. Recent studies showed that the tumor microenvironment has a crucial influence on tumor growth, and its reshaping characteristic provides therapeutic effects.
What Are the Components of the Tumor Microenvironment?
The composition of TME depends on the type of tumors. It includes immune cells, stromal cells, blood vessels, and extracellular matrix. The components interact with themselves and the tumor and help grow the tumor. TME is considered to provide the tumor with all nutrients for its growth.
Immune Cells: Immune cells are an essential component of TME. They either promote or suppress tumor growth. Immune cells are mainly divided into two categories.
Adaptive Immune Cells: These cells get activated on exposure to specific antigens and use immunological memory to test the threat and increase the immune responses. These are T, B, and natural killer (NK) cells.
Innate Immune Cells: These provide a non-specific defense mechanism that comes into action within an hour of entry of antigens into the body. Innate immune cells are macrophages, neutrophils, and dendritic cells.
T Cells: Every T cell forms its T cell receptor (TCR) that helps identify the specific antigen. There are different types of T cells present in TME that influence tumorigenesis. Cytotoxic T-cells (CD8+) help in identify and destroy the tumor cells. The presence of cytotoxic cells shows a favorable prognosis among individuals affected with cancer. These cells help in suppressing angiogenesis by secreting interferon-gamma (IFN-ɣ). CD4+ T cells get differentiated into T helper 1 (Th1) cells, and increased levels of Th1 cells indicate positive outcomes among cancer patients. Regulatory T cells (Tregs) suppress the inflammatory response and help control autoimmunity. The presence of Tregs in TME shows the promotion of cancer growth or development by reducing antitumor immune response.
B Cells: B cells are immune cells that help in antibody production, antigen presentation, and secretion of cytokines. These are usually present at the margins of tumors, in lymph nodes, and close to the TME. Infiltrating B cells are few in TME. B cells can have both pro-effects and antitumorogenic effects.
Natural Killer Cells: Natural killer cells are more efficient in killing tumor cells in the circulation. These are found to be less efficient in TME.
Macrophages: Macrophages are important components of the immune system. These can help in the progress of the tumor with TME. They can promote new blood vessel formation in TME.
Neutrophils: Neutrophils are important and form 70% of leukocytes. They provide the first line of defense against many pathogens. In the case of cancer, depending on the tumor type and stage of tumor development, they can either suppress or promote tumor cells.
Dendritic Cells: Dendritic cells play an important role in the immune system as antigen-presenting cells. They help in identify, capture, and present antigens to T cells. The TME shapes the fate of dendritic cells by providing an environment that either creates an immune response or accepts the tumor cells.
Stromal cells: Cancer cells incorporate many cells from endogenous tissue stroma and promote tumor formation. Stromal cells include vascular endothelial cells, fibroblasts, adipocytes, and stellate cells. When these stromal cells get recruited in TME, they secrete factors that influence angiogenesis, proliferation, invasion, and metastasis.
Endothelial Cells: Vascular endothelium is a monolayer of endothelial cells that helps form blood vessels. Vascular endothelium helps carry water and nutrients, maintain metabolic homeostasis, carry immune cells, and help form blood vessels.
Initially, tumor cells depend on passive diffusion of gas exchange and transportation of nutrients. When the tumor volume becomes 1-2mm3, there may be the development of insufficient oxygen, and accumulation of metabolic wastes takes place in TME. As a result, TME becomes hypoxic and acidic. To fight hypoxia and acidification, tumors must develop their blood supply. Blood vessels formed in the TME are not matured and lack cell-to-cell connections. Hence, tumor cells can easily extravasate.
Cancer-Associated Fibroblasts: Cancer-associated fibroblasts play a role in facilitating crosstalk between cancer cells and TME—these help in promoting immunosuppressive phenotype through the production of immune modulatory chemokines and cytokines.
Adipocytes: Adipocytes help regulate energy balance and store excess energy as fat. These cells show its effects on TME through the secretion of metabolites, enzymes, hormones, growth factors, and cytokines.
Stellate Cells: Stellate cells are present in the liver and pancreas. When there is an injury, they are transformed into myofibroblasts. When there is a hepatocellular carcinoma, hepatic stellate cells promote crosstalk with TME.
Extracellular Matrix: The extracellular matrix plays an important function in TME. It mainly provides a physical stand for cells. It plays a main role in tumor cell dispersal.
Exosomes: Exosomes are microvesicles similar to the original cells, containing protein, RNA, DNA, and lipids. Their role in TME is to promote cross-talk between cancer cells and stromal cells. These cells promote inflammation, tumor progression, angiogenesis, and metastasis within TME.
Therapeutically Targeting TME: Advanced treatments for cancer have changed in recent years. New drugs are formed in such a way that they target cells in the TME. Immune checkpoint blockade (ICB) is an antibody-based therapy that targets immune cells in the TME.
Therapeutic use of dendritic cell vaccination to target dendritic cells in TME is done in prostate cancer. The Provenge protocol uses monocytes, which are differentiated into dendritic cells and activated to help in specific cancers.
Another way to fight against oxygen deprivation is to target angiogenesis. Antiangiogenic therapy targeted the vascular endothelial growth factor (VEGF)/VEGFR signaling axis.
Understanding TME may help in targeting new strategies for treating cancer.
Conclusion:
TME surrounding the tumor consists of different types of cell components that play different roles. TME is always present around the tumor cell and many changes may be observed around the cells. Hence, understanding the TME and its components is necessary for managing cancer treatments.
